The present invention comprises a transdermal patch for the administration of drugs percutaneously. In particular, the invention is useful for the administration of the drug albuterol, a .beta..sub.2 adrenergic agonist, which is useful, among other things, in the treatment of asthma by virtue of its action of inducing bronchodilation.
The practicality of administering a given drug percutaneously on a continuous basis depends upon the concentration of drug in the blood that is required to provide the desired pharmacologic effect, the degree to which the skin is permeable to the drug, and the amount of skin surface area that is available for drug administration.
The skin surface area which is available for drug administration, while theoretically being unlimited, is, for practical reasons, typically confined to a range of from about five square centimeters to about 100 square centimeters. With the available skin surface area fixed within this range, the matter then narrows as to whether sufficient drug will pass through that much skin surface area to provide the desired therapy. If it will, then it may not be difficult to effectively administer the drug percutaneously. If, however, the inherent permeability of the skin to the drug is so high or so low that too much or too little drug will pass through that area of skin, then the rate of administration of the drug to the skin must be controlled, or the permeability of the skin to the drug must be increased, as the case may be, to make percutaneous administration practical.
The present invention involves a drug delivery system in which the percutaneous administration of the active drug component is enhanced by the presence of a diffusion enhancer.
Systemically active drugs are conventionally administered either orally or by injection, with the primary objective of either mode being to achieve a given desired blood level of drug in circulation over a period of time.
These prior conventional methods of administering drugs to patients, however, possess certain shortcomings resulting in the failure to this goal.
The oral route of drug administration, for example, is inadequate for several reasons, even if the drug is administered to the patient at periodic intervals according to a well-defined schedule.
The rate of absorption of drug through the gastrointestinal tract is affected by both the contents in the tract and the passage of time as the drug travels through the small intestine. Therefore, such variables as whether the drug is administered before or after eating, and the type and quantity of food eaten, for example, high or low fat content, or whether the drug is administered before or after a bowel movement, affect the rate of absorption of the drug which takes place in the small intestine.
Additionally, the time of passage of drug through the small intestine is affected by the rate of peristaltic contraction, adding further uncertainty.
Also important is the rate of circulation of blood to the small intestine, and the fact that many drugs administered by this route are rendered inactive by gastric acid and digestive enzymes of the gastrointestinal tract or liver, where the drug can be metabolized to an inactive product.
These factors make it difficult to achieve a desired time course of concentration of drug in the blood.
The most widely-used dosage form of albuterol, an orally-administered, instant-release (IR) tablet, is administered to a patient every 6 hours. The controlled-release (CR) albuterol tablet is administered to a patient ever 12 hours.
A significant disadvantage associated with the oral administration of albuterol is that orally-administered albuterol undergoes extensive first pass metabolism, probably in the gastrointestinal tract, with the result that the bioavailability of the drug formulation is reduced from a potential bioavailability of 100 percent to as low as 10 percent.
The most inevitable result of the oral administration of drugs through the gastrointestinal tract is that the level of drug in circulation surges to a peak level at the time the drug is administered, followed by a decline in drug concentration in the blood and body compartments. Thus, a plot of a drug in circulation versus time after the administration of several tablets of the drug per day will have the appearance of a series of peaks which may surpass the toxic threshold of the drug, and valleys which may fall below the critical point needed to achieve the desired pharmacologic or therapeutic effect of the drug, rather than a horizontal straight line indicating a steady-state concentration (C.sub.ss) of the drug in circulation.
The administration of drugs by injection likewise entails certain disadvantages. For example, very strict asepsis must be maintained in order to avoid infection of the blood, the vascular system and the heart. Drug administration by poor intravenous injection technique may result in perivascular injection, when that was not intended. The typical result of injection of a drug into the blood is a sudden rise in the blood concentration of the drug followed by an uncontrollable decline in drug concentration. Additionally, administration of drugs by injection is inconvenient and painful.
Other dosage forms for systemic administration of drugs, such as rectal suppositories and sublingual lozenges, also produce non-uniform levels of the therapeutic agent in circulation. These dosage forms require great patient cooperation and have low patient acceptability, resulting in decreased patient compliance with a prescribed drug regimen, which is the most common failure of drug therapy.
To avoid the problems discussed above, a new branch of drug delivery has developed in which systemically-active drugs are administered through the skin or mucosa of a patient. Uncertainties of administration through the gastrointestinal tract, and the inconvenience of administration by injection, are decreased or eliminated by this system of drug administration. The ease of application, and simplicity of removal, of such a drug delivery system produces a desirable psychological effect on the patient. This means better patient cooperation, resulting in more effective therapy. Because a high concentration of drug never enters the body, problems with pulse entry (varying levels of drug in the patient's circulation, depending upon the time of drug administration) are overcome.
Despite these advantages of administering systemically-active drugs through the skin, many problems exist with prior art devices designed for this purpose. Many such devices do not provide a continuous administration of drug to the patient, or a continuous delivery rate. Also, many such devices are irritating to the patient's skin or mucosa and/or have limited application to a relatively narrow group of therapeutic drugs. Frequently, new application systems must be designed for drugs which are incompatible with prior art application systems.
The release of a drug from a topical preparation can be materially affected by the vehicle in which it is applied. Correct formulation of a topical agent will ensure that it exerts its maximal activity, while an incorrect formulation of the agent may reduce its activity, or even render a potent drug essentially ineffective.
The primary requirement for topical drug therapy is that a drug incorporated in a vehicle reach the skin surface at an adequate rate and in sufficient amounts. The drugs must then penetrate the outer horny layer of the skin.
Drug penetration through the skin depends upon release of the drug from the topical delivery device and transport of the drug across the skin barrier. In most cases, the rate-limiting step is skin transport. However, formulation changes can affect both of these steps.
Transport of drug substances through the skin is affected by a variety of factors. For diffusion to occur, the drug must be in solution. Thus, solubility of the drug in the fluids in and around the epidermal cells is of great significance.
The polarity of the drug molecules must also be considered. When hydrated, the stratum corneum contains approximately 75% water, 20% protein and 5% lipid. During hydration, water accumulates near the outer surface of the protein filaments. Polar molecules are believed to pass through this aqueous layer, while nonpolar molecules probably dissolve in, and between, the protein filaments.
The oil-water partition coefficient is also important. If a substance is more soluble in the stratum corneum than in the vehicle in which it is dissolved, then transfer to the former will be favored. In vitro and in vivo studies support the postulate that the release of a drug will be facilitated by using vehicles having a low affinity for the penetrant. Thus, in formulation, care is necessary to ensure that the benefits of drug solubility in relation to skin penetration are not reduced by the use of excipients which have too high an affinity for the drug.
A further factor which has been shown to influence drug effectiveness, and which can be manipulated by the formulator, is the level of hydration of the stratum corneum. Hydration results from water diffusing from underlying epidermal layers or from perspiration that accumulates under an occlusive vehicle. In general, increasing the moisture content of the stratum corneum increases the rate of passage of all substances which penetrate the skin.
Researchers working in the art have conducted studies of the effects of vehicles containing substances which materially affect skin penetration. A range of agents has been recorded as having accelerant action, in particular propylene glycol, surface active agents, dimethylsulfoxide, and dimethylacetamide. These substances, however, have certain drawbacks, including skin irritation potential. Their use to date has been limited.
B. Idson, Cosmetics and Toiletries 95, 59 (1980), has concluded that the factors affecting drug penetration into the skin and, consequently, in most cases effectiveness, are complex. The vehicle that provides ideal conditions for one drug may prove unsatisfactory for another.
The present invention seeks to overcome prior problems with the continuous administration of a drug to a patient, and with the delivery rate of the drug in general, and has been found to work particularly well with adrenergic agonists, and especially well with albuterol, a selective .beta..sub.2 adrenergic agonist.
Another object of this invention is to provide a device for the administration of albuterol to a patient in a reliable and easily-applied device for continuously administering the drug to the patient in controlled quantities through the patient's intact skin or mucosa.
Another object of this invention is to provide for such a drug delivery device which will cause little, if any, dermal or mucosal irritation to the patient.
Another object of this invention is to provide a drug delivery device which will be especially useful and acceptable in pediatric patients and geriatric patients.
A further object of this invention is to provide for a unitary, non-lamellar, single-layered drug delivery device.
Yet another object of this invention is to provide a drug administration device which will provide a continuous dosing of the drug to the patient over a 24-hour period.
The transdermal drug administration patches of the present invention generally provide a continuous administration of drug to the patient. In addition, these patches generally cause little or no dermal or mucosal irritation to the patient. Both of these qualities are significant advantages of the patches of the present invention in comparison with many of the transdermal drug administration systems known in the art. Many of the prior art devices designed to deliver systemically active drugs through the skin or mucosa of a patient fail to provide a continuous administration of the drug to the patient, and/or do not provide a continuous delivery rate of the drug to the patient. Even if a transdermal patch does administer a particular drug appropriately through the skin or mucosa of a patient, the patch will not be a desirable form of administration for the drug if the patch is irritating to the patient's skin or mucosa.
Prior to the invention of the transdermal albuterol patches described herein, researchers working in the field were unable to successfully deliver albuterol to a patient by means of a transdermal patch.
The transdermal albuterol patches of the present invention feature, in addition to the benefits already described above, a 100% skin bioavailability of drug to a patient, a good margin of safety in pediatric and geriatric patients and ease of administration.
Albuterol administered transdermally through a patch of the invention is useful for actual asthma therapy, rather than merely for prophylaxis. It is also useful in both pediatric age groups and geriatric populations, both of which require simple-to-administer regimens that do not rely on the responsibility or memory of the patient to comply with several daily dosage administrations of the drug, as is often needed with conventional tablets or capsules of albuterol. Transdermal albuterol therapy would also be useful after the treatment of an acute asthma attack to prevent the exacerbation of such an attack. Clinically, it would also be useful either as a substitute for intravenous therapy or as an improvement over oral therapy.
In addition to being convenient, transdermal albuterol therapy has a significant margin of safety. Significantly, an on-going therapy, such as with sustained-release oral formulations, could be interrupted if the average plasma level of the drug were too high. Once the patient was stabilized at a lower plasma level of drug, the transdermal albuterol patch would be beneficial to maintain consistent plasma levels of albuterol at a more desirable lower level.
Additionally, albuterol can be used transdermally as a tocolytic (obstetric) agent. Preterm labor occurs in approximately 10% of pregnancies. Commonly, beta-mimetic agents are employed for preterm labor. Albuterol is currently used for preterm labor, with the plasma albuterol levels needed for uterine relaxation being 8 to 33 nanograms of drug per milliliter. Such levels are within the range of albuterol delivered by the transdermal albuterol patches of the present invention.
The albuterol patches of the present invention also have the potential advantage of safety over the intravenous route of drug administration, and the further advantage of a more uniform dosing of the drug to the patient in comparison with the oral route of drug administration, during the sensitive and critical period during which labor occurs. Such a use of an albuterol patch of the invention may be adjunctive with bed rest and intravenous and oral agents, or may be primary therapy as a substitution for intravenous beta-mimetic agents.
Additionally, a transdermal albuterol patch of the invention may find usage as an emergency therapy for the treatment of urticaria (hives).
The usefulness of albuterol as a bronchodilator is not limited to the treatment of asthma. Albuterol can also be used as a bronchodilator in the treatment of bronchitis, chronic obstructive pulmonary disease and other obstructive pulmonary diseases.